Pharmacologic Evaluation of Antidepressant Activity and Synthesis of 2-Morpholino-5-phenyl-6H-1,3,4-thiadiazine Hydrobromide

Abstract

Substituted thiadiazines exert a reliable therapeutic effect in treating stress, and a schematic description of their ability to influence all aspects of a stress response has been depicted. This study was conducted to pharmacologically evaluate compound L-17, a substituted thiadiazine, (2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide) for possible anti-psychotic/antidepressant activity. Compound L-17 was synthesized by cyclocondensation of α-bromoacetophenone with the original morpholine-4-carbothionic acid hydrazide. Pharmacologic evaluations were conducted using methods described by E.F. Lavretskaya (1985), and in accordance with published guidelines for studying drugs for neuroleptic activity. Compound L-17 was evaluated for various possible mechanisms of action, including its effects on cholinergic system agonists/antagonists, dopaminergic neurotransmission, the adrenergic system, and 5-HT3 serotonin receptors. One or more of these mechanisms may be responsible for the beneficial effects shown by thiadiazine compounds in experiments conducted to evaluate their activity in models of acute stress and acute myocardial infarction.

Effects of 1,3,4-thiadiazine compound with antidepressant properties in ligation model of acute pancreatitis

“…This was confirmed by stress immobilization experiments where the substituted 1,3,4-thiadiazine L-17 lowered reac-tion to stress (Sarapultsev et al 2015) and by the results of pharmacological evaluation (Sarapultsev et al 2016). A report demonstrated that L-17 combined adrenergic, cholinergic and serotonin blockers and exerted its best effect in a similar concentration range to that used for the atypical antipsychotic agent Eglonyl (sulpiride) for antidepressants such as amitriptyline and in the alpha-blocker pyrroxanum (Sarapultsev et al 2016). These promising research results on the course of experimental AP and the ability to lower reaction to stress by the proven antistress/neuroleptic action of this compound have inspired this extended study's aim: to investigate the therapeutic mechanisms of L-17, with a histological, haematological, biochemical and immunohistochemical evaluation and an assessment of circulating cytokine levels.…”

“…The described action mechanisms of L-17 are similar in effect to atypical antipsychotics (Sarapultsev et al 2016), and this could explain its action on both the immune system and inflammatory response. The literature records that antidepressant drugs frequently affect the dysregulated immune response in depressed patients, mainly by improving the serum cytokine profile during therapy (Kenis and Maes 2002;Janssen et al 2010;Hannestad et al 2011); this may result from their influence on cytokine release (Kubera et al 2001a(Kubera et al , 2001b(Kubera et al , 2005.…”

“…This was confirmed by stress immobilization experiments where the substituted 1,3,4-thiadiazine L-17 lowered reac-tion to stress (Sarapultsev et al 2015) and by the results of pharmacological evaluation (Sarapultsev et al 2016). A report demonstrated that L-17 combined adrenergic, cholinergic and serotonin blockers and exerted its best effect in a similar concentration range to that used for the atypical antipsychotic agent Eglonyl (sulpiride) for antidepressants such as amitriptyline and in the alpha-blocker pyrroxanum (Sarapultsev et al 2016).…”

“…2-morpholino-5-phenyl-6H-1,3,4-thiadiazine hydrobromide (compound L-17) (Reaxys RN=14755889, CAS NUMBER 193208-23-0) from the group of substituted 1,3,4-thiadiazines studied in these experiments has proven a biological effect (Rantsev et al 2013;Sarapultsev et al 2014Sarapultsev et al , 2015Sarapultsev et al , 2016. The lethal dose of L-17 (LD50) is 434 mg/ kg (by weight), and the compound is a registered invention (United States Patent No 6313111 of 6 November 2001, PCT RF Patent No 2259371 of 27 August 2005.…”

“…The ability of substituted 1,3,4-thiadiazine compounds to lower stress reaction was previously described (Sarapultsev et al 2015), and their ability to act on both serotonin and adrenergic systems has been proposed (Sarapultsev et al 2016).. Here, a singular synchronized-action on serotonergic and adrenergic systems, also seen in psychotropic drugs, significantly enhanced their therapeutic effect (Arnsten 2004) because alpha-1 and serotonin (5HT2A) receptors are involved in the common phosphatidyl inositol/protein kinase C intracellular pathway via Gq proteins (Duman and Nestler 1995).…”